Variability in disease severity caused by a microbial pathogen is impacted by each
infection representing a unique combination of host and pathogen genomes. Here, we show that the outcome of invasive Streptococcus pyogenes
infection is regulated by an interplay between human
STING genotype and bacterial
NADase activity. S. pyogenes-derived
c-di-AMP diffuses via
streptolysin O pores into macrophages where it activates
STING and the ensuing type I IFN response. However, the enzymatic activity of the
NADase variants expressed by invasive strains suppresses
STING-mediated type I IFN production. Analysis of patients with necrotizing S. pyogenes
soft tissue infection indicates that a
STING genotype associated with reduced
c-di-AMP-binding capacity combined with high bacterial
NADase activity promotes a 'perfect storm' manifested in poor outcome, whereas proficient and uninhibited
STING-mediated type I IFN production correlates with protection against host-detrimental
inflammation. These results reveal an immune-regulating function for bacterial
NADase and provide insight regarding the host-pathogen genotype interplay underlying invasive
infection and interindividual disease variability.